Sequelae of Cardiopulmonary Bypass-Induced Pulmonary Injury
In the immediate post-operative period, children who have undergone surgery to repair a congenital heart lesion are highly vulnerable to a sudden or sustained increase in pulmonary vascular resistance. Following surgery, the reactivity of the pulmonary vasculature is increased such that vasospastic stimuli may cause sudden increases in pulmonary arterial pressure and resistance. These in turn may lead to acute right-sided heart failure, tricuspid regurgitation, systemic hypotension, myocardial ischemia, and increased airway resistance. In their full-blown form, such pulmonary hypertensive crises may be lethal. Milder stimulating events can precipitate milder crises that last longer and cluster, leading to prolonged stays in the Intensive Care Unit (ICU). Adatia & Beghetti (2009) Cardiol Young 19(4): 315-319.
Cardiopulmonary bypass (CPB) induced injury results from a principally humoral systemic inflammatory response induced by the bypass process. Seghaye (2003) Cardiol Young 13(3): 228-239; Day & Taylor (2005) Int J Surg 3(2): 129-140; Jaggers & Lawson (2006) Ann Thorac Surg 81(6): S2360-2366; Kozik & Tweddell (2006) Ann Thorac Surg 81(6): S2347-2354; Warren et al. (2009) J Cardiothorac Vasc Anesth 23(2): 223-231; Warren et al. (2009) J Cardiothorac Vasc Anesth 23(3): 384-393. The damage sustained by the lung and other tissues results in the serious clinical condition described herein.
Proportion of Children Undergoing CPB Who Develop Pulmonary Injury Sequelae to CPB
About one fifth to one third of juvenile patients undergoing cardiopulmonary bypass suffer from sequelae of cardiopulmonary bypass-induced pulmonary injury. Acute postoperative pulmonary hypertension is considered a key feature indicative of sequelae of cardiopulmonary bypass-induced pulmonary injury. Russell provides criteria to clinically significant pulmonary hypertension as either: (A) where the mean pulmonary arterial pressure was ≥50% of the mean systemic arterial pressure; or (B) where echocardiographic data indicated a similar degree of pulmonary hypertension. Russell et al. (1998) Anesth Analg 87(1): 46-51. This resulted in a figure of 13 of 36, or 36% of patients undergoing congenital heart repair surgery suffering from sequelae of cardiopulmonary bypass-induced pulmonary injury.
In another approach, Lindberg focused upon severe pulmonary hypertension by defining severe postoperative pulmonary hypertension as a mean pulmonary arterial pressure equal to or exceeding the level of mean systemic arterial pressure. Lindberg et al. (2002) J Thorac Cardiovasc Surg 123(6): 1155-1163. Overall, 2% of 1349 patients in their population met this stringent criteria. Lindberg discusses the presence of moderate cases of pulmonary hypertension, but did not specifically quantitate them. However, patients who qualified for full chart review either had a pulmonary arterial catheter in the ICU, spent more than four days on mechanical ventilation, or died. These patients, who likely had clinically significant pulmonary hypertension, totaled 224 in number, representing 17% of the population. Id.
A number of studies cite similar figures. Bando mentions about 30% percent of patients historically developed pulmonary hypertension while noting a more recent decrease, however the data in the paper suggest an about 17% rate. Bando et al. (1996) J Thorac Cardiovasc Surg 112(6): 1600-1607. Checchia stated that the exact incidence of pulmonary hypertension in children undergoing cardiac surgery remains unclear. Checchia et al. (2012) Pediatr Cardiol 33(4): 493-505. Checchia noted only one study where 11 of 20 infants developed postoperative pulmonary hypertension; when episodic pulmonary hypertension cases were also included, the proportion rose to 75%. Id.
Fate of Children Who Develop Post-Operative Pulmonary Hypertension
A study by Brown examined the fate of children who develop postoperative pulmonary hypertension and framed it in clinically and economically important terms. All possible risk factors for length of stay were examined in several multivariate models. The strongest factors, including pulmonary hypertension, were combined into a complications score. Both in the postoperative model and in the final model as part of the complications score, pulmonary hypertension was a strong predictor of prolonged length of stay. Prolonged length of stay has major economic consequences. Children who fell above the 95th percentile for length of stay accounted for 30% of bed days with three-times the mortality of children under the 95th percentile. In one center, 7.1% of patients used 50.1% of the total intensive care days and 47.7% of the total technology resources. Notably, 12% of patients required ICU stays of 14 days or longer. For all patients, the median stay was 3 days. In contrast, the median ICU stay of patients at or above the 95th percentile was 27 days. Consistent with this, the median duration of mechanical ventilation for patients at or above the 95th percentile was 23 days. Brown et al. (2003) Crit Care Med 31(1): 28-33.
Current Therapies for Sequelae of CPB-Induced Pulmonary Injury
Landis provided an evidence-based review of the various strategies in use to treat postoperative pulmonary hypertension in adult pulmonary bypass, concluding that only inhaled nitric oxide and possibly complement inhibitors provide any real value. Landis et al. (2014) J Extra Corpor Technol 46(3): 197-211. Other studies have focused upon pediatric cardiac surgery. Apostolakis et al. (2010) J Cardiothorac Surg 5: 1; Barst et al. (2010) Pediatr Cardiol 31(5): 598-606; Fraisse & Wessel (2010) Pediatr Crit Care Med 11(2 Suppl): S37-40; Taylor and Laussen (2010) Pediatr Crit Care Med 11(2 Suppl): S27-29; Bronicki & Chang (2011) Crit Care Med 39(8): 1974-1984; Fraisse et al. (2011) Intensive Care Med 37(3): 502-509; Checchia et al. (2012) Pediatr Cardiol 33(4): 493-505; Brunner et al. (2014) Pulm Circ 4(1): 10-24. The mainstay of current therapy remains inhaled nitric oxide (iNO). Nitric oxide, like most of the other therapies, is a reactive therapy that first requires a patient to develop the respiratory complications of cardiopulmonary bypass before therapy can be initiated. Moreover, inhaled nitric oxide has two main drawbacks; (A) inhaled nitric oxide has a marked rebound phenomenon when discontinued; and (B) when nitric oxide complexes with hemoglobin, it leads to methemoglobinemia. While phosphodiesterase 5 inhibitors such as sildenafil have been used to blunt the rebound of inhaled nitric oxide, the results have not been uniform.
Accordingly, there exists in the art a need for a more effective method for reducing the sequelae of CPB-induced pulmonary injury in a patient during surgery and postoperatively.